Acute myeloid leukemias (AML) are a heterogeneous disease sub-divided into cytogenetics and molecular subsets characterized by favorable and unfavorable response to current therapies. Fms-like tyrosine kinase 3 internal tandem duplication (FLT3/ITD) is a constitutively active tyrosine kinase expressed in 30% of all AMLs cases. FLT3/ITD-expressing cells are considered one of most “unfavorable subsets” of AML with no effective treatment, suggesting the urgent need for the development of new therapies.
Several lines of evidence suggest that genomic instability in myeloid malignancies is promoted by increased endogenous DNA damage and error-prone repair that lead to disease progression and resistance to therapy. Poly-(ADP)-ribose polymerase (PARP) participates in single strand break (SSB) repair, as well as highly error-prone pathway repair for double strand breaks (DSBs). Leukemia cells are sensitive to PARP inhibitors, such as ABT888 (Veliparib; Abbott Laboratories, North Chicago, Ill.), suggesting their dependence on PARP activity for survival. BMN673 (BioMarin Pharmaceuticals, San Rafael, Calif.) is a novel and highly potent PARP1/2 inhibitor that has been tested in clinical trials against solid tumors carrying a DSB repair deficiency, such as a BRCA1 mutation. Recently, it has been demonstrated that in addition to catalytic inhibition of PARP, PARP inhibitors induce cytotoxic PARP-DNA complexes that could be held responsible for their therapeutic effect. Such a mechanism has been reported for the PARP inhibitor BMN673 (Murai et al., 2014).
Recent studies have demonstrated that leukemia cell lines and primary cells that are resistant to tyrosine kinase inhibitors and therapy-resistant derivatives of ER/PR+ and ER/PR− breast cancer cells, including primary tissue biopsies for the latter, have increased activity of a highly error-prone and alternative DSB repair pathway termed alternative non homologous end-joining (ALT NHEJ). These cells also upregulate the steady state levels of PARP1 and DNA ligase IIIα, components involved in this pathway. These cells, as well as leukemia cells resistant to tyrosine kinase inhibitors, have increased sensitivity to the combination of PARP and DNA ligase IIIαinhibitors as demonstrated by an increased number of DSBs and significantly increased colonies in colony survival assays (Tobin et al., 2012; Tobin et al., 2013). These results suggest ALT NHEJ is a novel therapeutic target, closely dependent on PARP1, in breast cancers and leukemias which are dependent upon this mode of DNA repair for survival.